Source Documents in Clinical Trials_part1

1. By Valentyna Korniyenko

2. Definition of the Source Document
Asourcedocumentisadocumentinwhichdatacollectedfora
clinicaltrialisfirstrecorded.Thesedataareusuallylaterentered
intheCaseReportForm.
•TheICH-GCPGuidelinesdefinesourcedocuments
asOriginaldocuments,Data,andRecords(e.g.,hospital
records,clinicalandofficecharts,laboratorynotes,
memoranda,subjects'diariesorevaluationchecklists,
pharmacydispensingrecords,recordeddatafromautomated
instruments,copiesortranscriptionscertifiedafterverification
asbeingaccuratecopies,microfiches,photographic
negatives,microfilmormagneticmedia,x-rays,subjectfiles,
andrecordskeptatthepharmacy,atthelaboratoriesandat
medico-technicaldepartmentsinvolvedintheclinicaltrial).
(ICHE6Guidance,1.52)
•TheFDAdoesnotdefinetheterm"sourcedocument."
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3. There are Source Documents of 2 types:
•Electronic
•Paper
Electronicrecordmeansanycombinationoftext,graphics,data,
audio,pictorial,orotherinformationrepresentationindigitalform
thatiscreated,modified,maintained,archived,retrieved,or
distributedbyacomputersystem.
•21 CFR Part 11, Electronic Records; Electronic signatures (1997)
•Guidance for Industry: Part 11, Electronic Records; Electronic Signatures
− Scope and Application (2003)
•Guidance for Industry: Computerized Systems Used in Clinical
Investigations (2007)
•Guidance for Industry: Electronic Source Data in Clinical Investigations
(2013)
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Types of the Source Documents

4. In regards to Electronic Source Documents:
1)Requirements to the computer system (validation)
2)Requirements to electronic records (audit trail)
3)Requirements to electronic signatures
4)Requirements to users and technical support
4
Types of the Source Documents

5. 5
Types of the Source Documents
Paper Source Documents can be:
•Handwritten data on the pre-printed
forms which have been prepared in
advance
•Handwritten records
Inbothcasesthesourcedocuments
areonlytherecords,either
handwrittenorprintedout,withthe
originalhandwrittenInvestigator’s
signature.

6. While choosing the appropriate type of source documentation
for a clinical trial, the following aspects should be taken into
consideration:
•Design and organization of the Trial:
Inpatient, outpatient or combined?
Is a clinical site within one clinical department or
several departments (hospitals)?
Who coordinates the trial
(a chair of the Medical University / Academy or a
hospital)?
•Specifics of clinical research documents retention
(archiving) at a Medical Institution.
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Types of the Source Documents

7. ThemostcommontypeofSourceDocumentation(SD)is:
officialmedicaldocumentation,whichisusedinMedicalInstitutions
onregularbasis:
Medical History
Outpatient Medical Chart
Various Logs / Hospital Charts
(Functional Diagnostics Log –form № 047/о)
The templates of official medical documentation required in Ukraine
can be found in the following documents:
•Ministry of Healthcare Order # 110 dated 14 Feb 2012
•Ministry of Healthcare Order # 435 dated 29 May 2013
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Types of the Source Documents

8. 8
Types of the Source Documents

9. General GCP requirements to the Source Documents Verification
(SDV):
•The purpose of trial monitoring is to verify that the reported
trial data are accurate, complete, and verifiable from source
documents. (ICH E6, 5.18.1b)
•Ifallowedbytheinvestigationalplan(protocol),datamaybe
entereddirectlyontothecasereportforms.Thecasereport
formwouldthenbeconsideredasourcedocument.Ifthis
casereportformisthentransmittedtothesponsor,itis
necessaryforthestudysitetoretainacopytoensurethatthe
principalinvestigatorcanprovideaccesstothesource
documentstoamonitor,auditor,orregulatoryagency.
(ICHE6,6.4.9).
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GCP requirements to the Source
Documents Verification

10. 10
Challenge Aspects of Source Documents
Verification
The main challenges during SDV are:
•Informed Consent process
•SAE and AE reporting
•Inappropriate ways of
corrections and loss of audit trail
•Not properly certified copies
of original records
•Inclusion/exclusion criteria listed
but not really confirmed

11. •BeforehavingsignedtheInformedConsentForm(ICF),thepatientcan
undergoonlyroutinemedicalprocedureswhichareapplicableina
certainmedicalinstitutionforsuchcategoryofpatients.
•Thesubjectmustpersonallysign,dateandtimethelatestversionofthe
ECapprovedinformedconsentformbeforeanytrial-relatedprocedures
start.
•ThesubjectmustbegivensufficienttimetoreadtheICFandbegiven
theopportunitytoaskquestions(theInformedConsentprocessmustbe
fullydescribedinSD).
•ThePIorhis/herdesigneemustsign,dateandtimetheinformed
consentformonthesamedayasthesubject.
•Anoriginalsampleofthesigned,datedandtimedICF(andaddendumif
applicable)mustbegiventothesubject.Thesecondoriginalmustbe
filedintheISF.
Informed Consent Form

12. Situation №1
Amale,DOB27Feb1972,wasbroughttothehospitaladmissiondepartment
bytheambulanceat10:30.ThepreliminarydiagnosisisAcute
CerebrovascularEvent,dextralhemiparesis,coma.Lossofconsciousnessat
09:50onthewaytotheoffice.Theambulancewascalledforbythe
passersby.
11:00–thediagnosisisIschemicStrokeattheleftmiddlecerebralartery
circulationarea.Dextralhemiparesis.ComaI.
Recommended:thrombolytictherapy.
Thepatientisconsideredfortheparticipationintheclinicaltrailoftissue-type
plasminogenactivator.Thrombolysisshouldbeperformedwithin3hoursafter
symptomsonset.
Canthispatientbeincludedintotheclinicaltrial?
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Informed Consent Form

13. Answers №1
a)Ifitwaspossibletocontactpromptlyalegalrepresentativeorarelative,
he/shecanprovideanInformedConsent.Assoonasthepatientcomes
toconsciousness,InformedConsentofthepatientshouldbeobtained.
b)Incaseitwasimpossibletocontactalegalrepresentativeorarelative,
thepatientcannotparticipateintheclinicaltrial.
Inemergencysituations,whenpriorconsentofthesubjectisnotpossible,
theconsentofthesubject'slegallyacceptablerepresentative,ifpresent,
shouldberequested.Whenpriorconsentofthesubjectisnotpossible,and
thesubject’slegallyacceptablerepresentativeisnotavailable,enrolmentof
thesubjectshouldrequiremeasuresdescribedintheprotocoland/or
elsewhere,withdocumentedapproval/favorableopinionbytheIRB/IEC,to
protecttherights,safetyandwell-beingofthesubjectandtoensure
compliancewithapplicableregulatoryrequirements.Thesubjectorthe
subject'slegallyacceptablerepresentativeshouldbeinformedaboutthetrial
assoonaspossibleandconsenttocontinueandotherconsentas
appropriate(see4.8.10)shouldberequested.(ICHE6,4.8.15)
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Informed Consent Form

14. 14
Informed Consent Form
Situation №2
Apatient,whohasbeensuggestedparticipatingintheclinicaltrial,
cannotreadduetocataract.
CouldyoupleasedescribetheInformedConsentobtaining
procedureinthiscase?

15. 15
Informed Consent Form
Answers №2
•Thepatientshouldprovideamedicalrecordingprovinghis/herdiagnosis.The
InformedConsentobtainingprocedureisperformedinvolvinganimpartialwitness.
AfterhavingreadoutloudtheInformedConsentFormandexplainingitsessenceto
thepatient,andafterhavingobtainedtheoralinformedconsentofthepatientto
participateintheclinicaltrial,and,ifpossible,afterthepatienthassignedanddated
theICF,theimpartialwitnessshouldsignanddatetheICF.Inthiswaytheimpartial
witnesscertifiesthatICFinformationwascorrectlyprovidedandexplainedtothe
patient,andthatthepatientprovidedhis/hervoluntaryconsenttoparticipateinthe
clinicaltrial.
Ifasubjectisunabletoreadorifalegallyacceptablerepresentativeisunabletoread,
animpartialwitnessshouldbepresentduringtheentireinformedconsentdiscussion.
Afterthewritteninformedconsentformandanyotherwritteninformationtobeprovided
tosubjects,isreadandexplainedtothesubjectorthesubject’slegallyacceptable
representative,andafterthesubjectorthesubject’slegallyacceptablerepresentative
hasorallyconsentedtothesubject’sparticipationinthetrialand,ifcapableofdoingso,
hassignedandpersonallydatedtheinformedconsentform,thewitnessshouldsignand
personallydatetheconsentform.Bysigningtheconsentform,thewitnessatteststhat
theinformationintheconsentformandanyotherwritteninformationwasaccurately
explainedto,andapparentlyunderstoodby,thesubjectorthesubject'slegally
acceptablerepresentative,andthatinformedconsentwasfreelygivenbythesubjector
thesubject’slegallyacceptablerepresentative.(ICHE6,4.8.9)

16. 16
Informed Consent Form
Situation №3
Thepatientwiththediagnosisofschizophrenia,qualifiedasdisabled,is
consideredfortheparticipationintheclinicaltrial.
How the Informed Consent procedure should be conducted in this
case?
WhoshouldsigntheInformedConsentForm?

17. 17
Informed Consent Form
Answers №3
•TheInformedConsentFormshouldbesignedanddatedbythe
subject’slegallyacceptablerepresentative,and,ifpossible,bythe
patienthimself/herself.TheinvestigatorwhoconductedtheInformed
ConsentprocedureshouldalsosignanddatetheICF.Thepatient
shouldbeinformedaboutthetrialtotheextentcompatiblewiththe
subject’sunderstanding.
Whenaclinicaltrial(therapeuticornon-therapeutic)includessubjectswho
canonlybeenrolledinthetrialwiththeconsentofthesubject’slegally
acceptablerepresentative(e.g.,minors,orpatientswithseveredementia),
thesubjectshouldbeinformedaboutthetrialtotheextentcompatiblewith
thesubject’sunderstandingand,ifcapable,thesubjectshouldsignand
personallydatethewritteninformedconsent.(ICHE6,4.8.12)

18. 1.E6 Good Clinical Practice: Consolidated Guideline
4. Investigator
4.8 Informed Consent of Trial Subjects
2. 21 CFR Part 50: Protection of Human Subjects
(Informed Consent)
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Informed Consent Form